Endothelial cell phenotypes display remarkable heterogeneity in health and disease. An important goal in vascular biology is to understand the molecular mechanisms underlying the spatial and temporal modulation of endothelial cell phenotypes. We have recently demonstrated that: 1) forkhead transcription factors are constitutively expressed in endothelial cells, 2) VEGF, TNF-a and thrombin induce the phosphorylation of 1 or more of the forkhead proteins in primary human endothelial cells, and 3) the inducible phosphorylation of forkhead transcription factors is coupled to a reduction in target gene expression and alteration in endothelial cell function. Taken together, this data supports the hypothesis that forkhead transcription factors function as signal transducers in the endothelium, coupling short-term changes in the extracellular environment to downstream changes in gene expression. The overall goal of this project is to characterize the role for forkhead transcription factors in transducing extracellular signals within the endothelium. A more complete understanding of these mechanisms should provide a framework for tailoring and fine tuning therapeutic modalities in vascular disease states.